A variety of dermatological compositions have been suggested for skin whitening to counteract abnormal pigmentation occurring in various disorders. Such disorders include post inflammatory hyperpigmentation, (attributed to various preceding conditions such as infections, allergic reactions, mechanical injuries, reactions to medications, phototoxic eruptions, trauma for example burns, and inflammatory diseases such as lichen planus, lupus erythematosus, atopic dermatitis), melasma, periorbital darkening, pigmented keratosis, lentigo senilis, ephelides, chloasma, café au lait spots, liver spots, freckles and lesions observed in Addison's disease, hemochomatosis, piebaldism, and the like. In addition, there is an enormous demand within populations with genetically inherited dark skin to lighten their skin color.
In mammals, skin and hair color is primarily determined by the amount of melanin pigments that are synthesized by melanocytes within specialized organelles called melanosomes. There is no evidence for differences in melanosome biogenesis between follicular and epidermal melanocytes. Thus, in black hair follicles, melanocytes contain the largest number and most electron-dense melanosomes. In brown hair, bulb melanocytes are smaller, and in blonde hair melanosomes are poorly melanized (Slominski et al., 2004). Melanin synthesis (also termed melanogenesis) is controlled by at least three enzymes: tyrosinase, tyrosinase-related-protein 1 (TRP1) and tyrosinase-related-protein 2 (TRP2), among which tyrosinase has the key role of catalyzing the rate limiting steps of the hydroxylation reaction of tyrosine to L-DOPA and the oxidation reaction of L-DOPA into dopaquinone.
Melanogenesis and melanosome transfer from the melanocytes to the neighboring keratinocytes involve a complex network of regulatory processes, and are induced primarily by ultraviolet radiation. Solar radiation acts either directly on melanocytes or indirectly though the release of keratinocyte-derived melanocyte stimulating hormone (α-MSH), a potent inducer of melanogenesis both in vivo and in vitro (Englaro et al., 1998). α-MSH stimulates adenylate cyclase activity leading to an increase in cAMP level which elevates the expression of melanogenic enzymes, in particular that of tyrosinase (Hunt of al., 1994; Im et al., 1998; Lee et al., 2007). In contrast, inhibition of adenylate cyclase activity resulting in decreased levels of intracellular cAMP is associated with inhibition of melanogenesis and depigmentation (Choi et al., 2008; Lee et al., 2007). Keratinocyte growth factor (KGF), a paracrine mediator of human keratinocyte growth and differentiation, has been shown to induce melanosome transfer from melanocytes to keratinocytes through a phagocytic process (Cardinali et al., 2005).
Dermatological compositions which have been disclosed for hair and skin bleaching typically act by destroying or disrupting melanin granules, inhibiting melanin formation (such as by inhibiting tyrosinase or melanocyte activity), or both. Various skin whitening compositions are disclosed for example, in U.S. Pat. Nos. 5,980,904, 5,747,006, and 6,077,503. Many of these compositions contain harsh chemicals such as peroxides, acids or formaldehyde, or thiolated compounds such as glutathione, cysteine, mercaptosuccinic acid, mercaptodextran, and mercaptoethanol, which have an objectionable odor that makes products containing them undesirable for use.
Hydroquinone for topical application is approved in the United States for non-prescription use, and acts by suppressing melanocyte activity. U.S. Pat. No. 6,068,834 discloses hydroquinone-based compounds and compositions Hydroquinone, however, is oxidized by air, light, and tyrosinase itself, which adversely affects the shelf life of preparations containing it and its bioavailability upon application. Hydroquinone can cause burning, redness, sensitization and irritation in some individuals, particularly after application of quantities sufficient to cause skin bleaching. Oxidized products of hydroquinone have also been implicated in skin irritation and pigmentation rebound.
Retinoids and corticosteroids for topical use have been suggested as hypopigmenting agents, as have laser treatment and chemical peels, but these fall short of desirable responses. A combination therapy containing tretinoin and fluocinolone with hydroquinone has been disclosed (Willis, 2000). Kojic acid and arbutin have also been suggested (Draelos, 2007), but these weak tyrosinase inhibitors generally display low bioavailability. Furthermore, arbutin is ineffective at levels allowed by Japanese quasi-drug regulations, and kojic acid has been banned for quasi-drug usage in Japan due to its mutagenic properties (Boissy et al., 2005).
U.S. Pat. No. 7,019,029 discloses the use of hydroxythtronic acid derivatives alone or in combination with tetronic acid, hydroquinone, glycolic acid and/or ascorbyl palmitate as skin whiteners.
Various plant extracts have been disclosed for bleaching skin or for enhancing the appearance of fair skin, which have in some cases been used for centuries in Asia or Europe. U.S. Pat. No. 5,602,259 discloses a furanone extracted from Pinaceae plants for use in whitening skin by inhibiting melanin formation.
U.S. Pat. No. 5,905,091 discloses a composition comprising a carrier and a prostaglandin, and optionally comprising a lysosomotropic agent, a phosphodiesterase inhibitor, and/or methylxanthines, and a method of use thereof for stimulating synthesis of melanin in a human melanocyte thereby enhancing pigmentation of human skin.
U.S. Pat. No. 5,554,359 discloses a composition comprising a lysosomotropic agent, and optionally phosphodiesterase inhibitors, and/or methylxanthines for increasing synthesis of melanin in a human melanocyte thereby enhancing pigmentation of human skin.
Adenosine is an endogenous purine nucleoside ubiquitous in mammalian cells, which is an important regulatory compound that mediates many physiological effects via binding to its specific A1, A2 and A3 cell surface receptors. Interaction of adenosine with its receptors initiates signal transduction pathways, in particular that of the adenylate cyclase effector system, which utilizes cAMP as a second messenger. The A1 and A3 adenosine receptors, which are coupled to Gi proteins, inhibit adenylate cyclase and lead to a decrease in the level of intracellular cAMP, while the A2 adenosine receptor, which is coupled to Gs proteins, activates adenylate cyclase, thereby increasing cAMP levels (see for example, Fredholm et al., 2000).
The use of various adenosine receptor agonists and antagonists for treatment of different disease states and pathologies has been suggested, including for example, inflammation (Salvatore et al., 2000), neurodegeneration (Von Lubitz, 1999), asthma (Forsythe and Ennis, 1999), cardiac ischemia (Liang and Jacobson, 1998), and tumors (Yao et al., 1997).
U.S. Pat. No. 7,064,112 discloses the use of A3 adenosine receptor agonists for the prevention and treatment of leukopenia, and for the inhibition of abnormal cell growth and proliferation of tumor cells.
WO 2008/023362 discloses methods and compositions useful for treating cancer based on the combination of methotrexate and an A3 adenosine receptor agonist.
U.S. Pat. No. 7,465,715 discloses the use of A3 adenosine receptor agonists for the treatment of multiple sclerosis.
U.S. Pat. No. 7,465,715 discloses the use of A3 adenosine receptor agonists for inhibiting viral replication in cells.
U.S. Pat. No. 7,141,553 discloses the use of A3 adenosine receptor agonists for the treatment of inflammatory arthritis.
U.S. Pat. No. 5,998,423 discloses the use of adenosine A1 receptor antagonists and of adenosine A2 receptor agonists for increasing melanin production in skin or hair, and the use of adenosine A1 receptor agonists and adenosine A2 receptor antagonists for decreasing melanin production in skin or hair.
U.S. Patent Application Publication No. 2002/0115635 discloses a treatment method comprising administering to a subject an active agent selected from the group consisting of an adenosine A1 receptor ligand, an A2 adenosine receptor ligand, an adenosine A3 receptor ligand and a combination thereof. The method is disclosed to be effective for a variety of diseases and disorders, inter alia hair loss, which require elevation of GSK-3β activity for treatment.
U.S. Patent Application Publication No. 2007/0299032 discloses a method for maintaining and promoting hair thickening comprising applying to the scalp an external skin preparation containing one or more types of agents, inter alia the A3 adenosine receptor agonist Cl-IB-MECA.
U.S. Patent Application Publication No. 2008/0044439 discloses use of p38 inhibitors for treating skin conditions such as vitiligo, and describes adenosine A3 antagonists as possible p38 inhibitors.
There remains an unmet need for new compositions which modulate melanin production and thereby lighten the skin or hair or promote pigmentation for both pharmaceutical and cosmetic purposes.